Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as jak inhibitors

Abstract

The present invention provides cyclobutyl substituted pyrrolopyrimidines and pyrrolopyridines of Formula I: wherein X, Y, Z, L, A, R 5 , n and m are defined above, as well as their compositions and methods of use, that modulate the activity of Janus kinases (JAKs) and are useful in the treatment of diseases related to the activity of JAKs including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 X is CH or N; 
 Y is H, cyano, halo, C 1-3  alkyl, or C 1-3  haloalkyl; 
 Z is CR 4  or N; 
 W is CH or N; 
 when W is CH, then L is O, S, C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), C(═O)O, C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), S(═O) 2 N(R 7 ), or C(═NR 7a )N(R 7 ); or 
 when W is N, then L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), S(═O) 2 N(R 7 ), or C(═NR 7a )N(R 7 ); 
 R 1 , R 2 , R 3 , and R 4  are each independently H, hydroxy, halo, C 1-3  alkyl, or C 1-3  haloalkyl; 
 each R 5  is independently hydroxy, C 1-4  alkoxy, fluorine, C 1-4  alkyl, hydroxy-C 1-4 -alkyl, C 1-4  alkoxy-C 1-4 -alkyl, or C 1-4  fluoroalkyl; 
 each R 6  is, independently, H or C 1-4  alkyl; or 
 two R 6  groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; 
 R 7  is H or C 1-4  alkyl; 
 R 7a  is H, OH, CN, C 1-4  alkoxy, or C 1-4  alkyl; 
 or R 7  and R 7a , taken together with the C(═N)N moiety to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring; 
 A is H, C 1-6  alkyl, C 3-10  cycloalkyl, C 2-10  heterocycloalkyl, C 6-10  aryl, or C 1-10  heteroaryl; wherein said C 1-6  alkyl, C 3-10  cycloalkyl, C 2-10  heterocycloalkyl, C 6-10  aryl, and C 1-10  heteroaryl are each optionally substituted with p independently selected R 8  substituents; wherein p is 1, 2, 3, 4, or 5; provided when L is O, S, C(═O), C(═O)O, S(═O), or S(═O) 2 , then A is not H; 
 each R 8  is independently selected from halo, cyano, nitro, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, C 1-10  heteroaryl-C 1-4 -alkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR e R f , —C(═O)R b , —C(═O)OR a , —C(═O)NR e R f , —OC(═O)R b , —OC(═O)NR e R f , —NR e R f , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c S(═O) 2 R d , and —NR c S(═O) 2 NR e R f ; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g  groups; 
 each R a , R c , R d , R e , and R f  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  hetero cycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g  groups; 
 each R b  is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  hetero cycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g  groups; 
 each R g  is independently selected from halo, cyano, nitro, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  hetero cycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  hetero aryl, C 1-7  heteroaryl-C 1-3 -alkyl, —OR a1 , —SR a1 , —S(═O)R b1 , —S(═O) 2 R b1 , —S(═O) 2 NR e1 R f1 , —C(═O)R b1 , —C(═O)OR a1 , —C(═O)NR e1 R f1 , —OC(═O)R b1 , —OC(═O)NR e1 R f1 , —NR e1 R f1 , —NR c1 C(═O)R d1 , —NR c1 C(═O)OR d1 , —NR c1 S(═O) 2 R d1 , and —NR c1 S(═O) 2 NR e1 R f1 ; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R h  groups; 
 each R a1 , R c1 , R d1 , R e1 , and R f1  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R h  groups; 
 each R b1  is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R h  groups; 
 each R h  is independently selected from cyano, halo, hydroxy, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, hydroxy-C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, cyano-C 1-4  alkyl, thio, C 1-6  alkylthio, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, carbamyl, C 1-6  alkylcarbamyl, di(C 1-6  alkyl)carbamyl, carboxy, C 1-6  alkylcarbonyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonylamino, C 1-6  alkylsulfonylamino, aminosulfonyl, C 1-6  alkylaminosulfonyl, di(C 1-6  alkyl)aminosulfonyl, aminosulfonylamino, C 1-6  alkylaminosulfonylamino, di(C 1-6  alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6  alkylaminocarbonylamino, and di(C 1-6  alkypaminocarbonylamino; 
 m is 0, 1, or 2; and 
 n is 0, 1, 2, 3, or 4. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 X is CH or N;   Y is H, cyano, halo, C 1-3  alkyl, or C 1-3  haloalkyl;   Z is CR 4  or N;   W is CH or N;   when W is CH, then L is O, S, C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), C(═O)O, C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), or S(═O) 2 N(R 7 ); or   when W is N, then L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), or S(═O) 2 N(R 7 );   R 1 , R 2 , R 3 , and R 4  are each independently H, hydroxy, halo, C 1-3  alkyl, or C 1-3  haloalkyl;   each R 5  is independently hydroxy, C 1-4  alkoxy, fluorine, C 1-4  alkyl, hydroxy-C 1-4 -alkyl, C 1-4  alkoxy-C 1-4 -alkyl, or C 1-4  fluoroalkyl;   each R 6  is, independently, H or C 1-4  alkyl; or   two R 6  groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;   R 7  is H or C 1-4  alkyl;   A is C 1-6  alkyl, C 3-10  cycloalkyl, C 2-10  heterocycloalkyl, C 6-10  aryl, or C 1-10  heteroaryl; wherein said C 1-6  alkyl, C 3-10  cycloalkyl, C 2-10  heterocycloalkyl, C 6-10  aryl, and C 1-10  heteroaryl are each optionally substituted with p independently selected R 8  substituents; wherein p is 1, 2, 3, 4, or 5;   each R 8  is independently selected from halo, cyano, nitro, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, C 1-10  heteroaryl-C 1-4 -alkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR e R f , —C(═O)R b , —C(═O)OR a , —C(═O)NR e R f , —OC(═O)R b , —OC(═O)NR e R f , —NR e R f , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c S(═O) 2 R d , and —NR c S(═O) 2 NR e R f ; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g  groups;   each R a , R c , R d , R e , and R f  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  hetero cycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g  groups;   each R b  is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -alkyl, C 2-10  heterocycloalkyl, C 2-10  hetero cycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-4 -4-alkyl, C 2-10  heterocycloalkyl, C 2-10  heterocycloalkyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-10  heteroaryl, and C 1-10  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g  groups;   each R g  is independently selected from halo, cyano, nitro, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  hetero cycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  hetero aryl, C 1-7  heteroaryl-C 1-3 -alkyl, —OR a1 , —SR a1 , —S(═O)R b1 , —S(═O) 2 R b1 , —S(═O) 2 NR e1 R f1 , —C(═O)R b1 , —C(═O)OR a1 , —C(═O)NR e1 R f1 , —OC(═O)R b1 , —OC(═O)NR e1 R f1 , —NR e1 R f1 , —NR c1 C(═O)R d1 , —NR c1 C(═O)OR d1 , —NR c1 S(═O) 2 R d1 , and —NR c1 S(═O) 2 NR e1 R f1 ; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R h  groups;   each R a1 , R c1 , R d1 , R e1 , and R f1  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R h  groups;   each R b1  is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-3 -alkyl, C 2-7  heterocycloalkyl, C 2-7  hetero cycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7  heteroaryl, and C 1-7  heteroaryl-C 1-3 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R h  groups;   each R h  is independently selected from cyano, halo, hydroxy, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, thio, C 1-6  alkylthio, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, carbamyl, C 1-6  alkylcarbamyl, di(C 1-6  alkyl)carbamyl, carboxy, C 1-6  alkylcarbonyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonylamino, C 1-6  alkylsulfonylamino, aminosulfonyl, C 1-6  alkylaminosulfonyl, di(C 1-6  alkyl)aminosulfonyl, aminosulfonylamino, C 1-6  alkylaminosulfonylamino, di(C 1-6  alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6  alkylaminocarbonylamino, and di(C 1-6  alkyl)aminocarbonylamino;   m is 0, 1, or 2; and   n is 0, 1, 2, 3, or 4.   
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is N. 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH. 
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein L is O. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is cyano. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4  are each H. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0. 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, 1,2-dimethylpropyl, 1-(tert-butyl)methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a tetrahydropyran ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, a pyrimidine ring, a thiazole ring, or a pyrazine ring; each of which is optionally substituted with p independently selected R 8  substituents; provided when L is O, S, C(═O), C(═O)O, S(═O), or S(═O) 2 , then A is not H. 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 8  is independently selected from halo, cyano, C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, C 2-7  heterocycloalkyl, —OR a , —C(═O)OR a , or —NR e R f ; wherein said C 1-6  alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R g  groups; and wherein each R a , R e , and R f  is independently selected from H, C 1-6  alkyl, and C 1-6  haloalkyl. 
     
     
         18 - 25 . (canceled) 
     
     
         26 . The compound accordingly to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 X is N;   Z is N;   R 1 , R 2 , and R 3  are each H;   Y is cyano;   W is N and L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), S(═O) 2 , or S(═O) 2 N(R 7 ); or   W is CH and L is O;   R 6  is H;   R 7  is H or methyl;   A is methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, 1,2-dimethylpropyl, 1-(tert-butyl)methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a tetrahydropyran ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, a pyrimidine ring, a thiazole ring, or a pyrazine ring; each of which is optionally substituted with p independently selected R 8  substituents;   each R 8  is independently selected from halo, cyano, C 1-6  alkyl, C 1-6 haloalkyl, C 3-7  cycloalkyl, C 2-7  heterocycloalkyl, —OR a , —C(═O)OR a , or —NR e R f ; wherein said C 1-6  alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R g  groups; and wherein each R a , R e , and R f  is independently selected from H, C 1-6  alkyl, and C 1-6 haloalkyl;   each R g  is independently selected from C 2-7  heterocycloalkyl, —OR a1 , —NR e1 R f1 ; wherein said C 2-7  heterocycloalkyl is optionally substituted by 1 or 2 R h  groups independently selected from fluoro, OH, C 1-3  alkyl, C 1-3  alkoxy, and hydroxy-C 1-4  alkyl; and wherein each R a1 , R e1  and R f1  are independently selected from H, C 3-7  cycloalkyl, and C 1-6  alkyl;   p is 1, 2, or 3;   m is 1; and   n is 0.   
     
     
         27 . The compound according to  claim 1 , wherein said compound has Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The compound according to  claim 1 , wherein said compound has Formula V: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The compound according to  claim 1 , selected from:
 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-fluorobenzonitrile;   3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile;   4-{3-(cyano methyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine-1-carboxamide;   {3-(4-{[(2S)-2-methylpyrrolidin-1-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-(4-{[(2S)-2-ethylpyrrolidin-1-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   [1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;   {3-[4-(3,5-difluorobenzoyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[(2-chloro-5-fluoropyridin-3-yl)carbonyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[(5-fluoropyridin-3-yl)carbonyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[2-(difluoromethyl)-3-fluoroisonicotinoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-5-fluorobenzonitrile;   [1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;   [1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;   {3-[4-(3,4-difluorobenzoyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-[4-(2-chloro-3,6-difluoro benzyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[3-fluoro-5-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[2-fluoro-4-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)cyclobutyl}acetonitrile;   {3-(4-{[6-(difluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[2-fluoro-3-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[(5-fluoropyridin-3-yl)methyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[(2-isopropylpyrimidin-4-yl)carbonyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[4-fluoro-3-(trifluoromethoxy)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[4-chlorobenzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-{4-[2-fluoro-4-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N,N-dimethylpiperazine-1-carbo xamide;   {3-(4-{3-[(dimethylamino)methyl]-5-fluorobenzoyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-(4-{3-[(dimethylamino)methyl]-5-fluorobenzyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-[4-(ethylsulfonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N,N-dimethylpiperazine-1-sulfonamide;   4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-ethyl-N-methylpiperazine-1-carboxamide;   {3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-[4-(3-fluoro-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {3-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   [1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile-d1; and   or a pharmaceutically acceptable salt of any of the aforementioned.   
     
     
         30 . The compound of  claim 1 , selected from:
 3-[(4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-5-[(dimethylamino)methyl]benzonitrile;   3-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1yl]cyclobutyl}piperazin-1-yl)methyl]-5-[(dimethylamino)methyl]benzonitrile;   3-[(4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-[(dimethylamino)methyl]benzonitrile;   {trans-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[(ethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   6-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid;   {trans-3-(4-{[6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[(methylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[(dimethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(amino methyl)-2-(trifluoro methyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[(isopropylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[(cyclobutylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(methoxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(1-amino cyclobutyl)-2-(trifluoro methyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(1-amino cyclobutyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[1-(dimethylamino)cyclobutyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-[1-(dimethylamino)cyclobutyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(dimethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(methylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(1-methoxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-[1-(methylamino)cyclobutyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   2-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-6-(trifluoromethyl)isonicotinonitrile;   {trans-3-(4-{[6-(1-hydroxycyclobutyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(4,5-dihydro-1H-imidazol-2-yl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(methoxymethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isopropyl-N-methylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-methyl-N-propylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-ethylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[3-(dimethylamino)propyl]-N-methylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopropyl-N-methylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-methyl-N-(2,2,2-trifluoro ethyppiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isopropylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(trans-4-hydroxycyclo hexyl)piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(3R)-tetrahydro furan-3-yl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(2-hydroxycyclopentyl)piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S,2R)-2-hydroxycyclopentyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopentylpiperazine-1-carboxamide;   {trans-3-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(cyclopropylmethyl)piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1,2-dimethylpropyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1,2-dimethylpropyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-cyclopropylethyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1-cyclopropylethyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopropylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclobutylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(2,2-dimethylpropyl)piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isobutylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1-methylpropyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-methylpropyl]piperazine-1-carboxamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclobutylpiperazine-1-carboxamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1-methylpropyl]piperazine-1-carboxamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-methylpropyl]ppiperazine-1-carboxamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopropylpiperazine-1-carboxamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isopropylpiperazine-1-carboxamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopentylpiperazine-1-carbo xamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1,2-dimethylpropyl]ppiperazine-1-carbo xamide;   4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1,2-dimethylpropyl]piperazine-1-carbo xamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-methylpiperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]piperazine-1-carboxamide;   4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-(trifluoromethyl)propyl]piperazine-1-carboxamide;   [trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;   [trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;   N′-cyano-4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N,N-dimethylpiperazine-1-carboximidamide;   {trans-3-[4-(methylsulfonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   isopropyl 4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazine-1-carboxylate;   {cis-3-(4-{[4-(methoxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(methoxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(tert-butylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[4-[(tert-butylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(dimethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(methylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   2-[(1-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinonitrile;   2-[(1-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinonitrile;   {cis-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   3-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-5-[(dimethylamino)methyl]benzonitrile;   {cis-3-(4-{[6-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(morpholin-4-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   3-[(1-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-5-[(dimethylamino)methyl]benzonitrile;   {cis-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)phenoxy]piperidin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-{4-[3-[(diethylamino)methyl]-5-(trifluoromethyl)phenoxy]piperidin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{3-(difluoromethyl)-5-[(dimethylamino)methyl]phenoxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-[4-({6-chloro-4-[(dimethylamino)methyl]pyridin-2-yl} oxy)piperidin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-[(dimethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-[(ethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-[(3-hydroxyazetidin-1-yl)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-methyl-2-(trifluoro methyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(aminomethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   4-{trans-3-(cyano methyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]piperazine-1-carbo xamide;   {trans-3-(4-{[4-{[(2-hydroxy-1,1-dimethylethyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-{[(2-hydroxyethyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-{[(3-hydroxypropyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(azetidin-1-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(morpholin-4-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-[(3,3-difluoropyrrolidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrro lidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {trans-3-(4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   {cis-3-(4-{[4-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; and   {trans-3-(4-{[4-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;   or a pharmaceutically acceptable salt of any of the aforementioned.   
     
     
         31 - 33 . (canceled) 
     
     
         34 . A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A method according to  claim 34 , wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2. 
     
     
         36 . A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A method according to  claim 36 , wherein said autoimmune disease is a skin disorder, psoriasis, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder. 
     
     
         38 - 41 . (canceled) 
     
     
         42 . A method according to  claim 36 , wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, lymphoma, leukemia, or multiple myeloma. 
     
     
         43 . (canceled) 
     
     
         44 . A method according to  claim 36 , wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), myelofibrosis, primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD). 
     
     
         45 - 46 . (canceled) 
     
     
         47 . A method according to  claim 36 , wherein said bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormonal imbalance, bone resorption associated with hormonal therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer.